mTORC2-driven chromatin cGAS mediates chemoresistance in colorectal cancer

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited. However, the mechanisms underlying cGAS recruitment to chromatin and the functions of chromatin-bound cGAS (ccGAS) remain unclear. Here, we demonstrate that mTORC2-mediated serine 37 phosphorylation promotes human cGAS chromatin localization, regulating colorectal cancer cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions to regulate expression of genes involved in glutaminolysis and DNA replication. Knockdown of ccGAS inhibits colorectal cancer cell growth but induces chemoresistance under fluorouracil exposure both in vitro and in vivo. Moreover, inhibition of kidney-type glutaminase (KGA), a downstream target of ccGAS, overcomes chemoresistance induced by ccGAS knockdown in human and murine colorectal cancer. Thus, our study demonstrates that ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning, and illustrates that simultaneously targeting mTORC2-ccGAS and KGA provides a promising theraputic strategy to eliminate quiescent resistant cancer cells.

环GMP-AMP合酶（cyclic GMP-AMP synthase, cGAS）是一种胞质DNA感受器，可启动依赖STING的天然免疫应答，且能紧密结合染色质，其催化活性在此过程中受到抑制。然而，cGAS被招募至染色质的具体机制，以及结合染色质的cGAS（ccGAS）的功能仍不明确。本研究证实，mTORC2介导的丝氨酸37位磷酸化可促进人cGAS的染色质定位，并在不依赖STING的情况下调控结直肠癌细胞的生长与耐药性。我们发现，ccGAS可在特定染色质区域招募SWI/SNF复合物，从而调控参与谷氨酰胺分解代谢与DNA复制的基因表达。敲低ccGAS可抑制结直肠癌细胞的生长，但在体外与体内实验中，均会在氟尿嘧啶处理下诱导化疗耐药性。此外，作为ccGAS下游靶标的肾型谷氨酰胺酶（kidney-type glutaminase, KGA）的抑制剂，可克服ccGAS敲低在人类与小鼠结直肠癌中诱导的化疗耐药性。综上，本研究表明ccGAS可通过表观遗传模式调控协调结直肠癌的可塑性与获得性化疗耐药性，并揭示同时靶向mTORC2-ccGAS与KGA或是清除静息耐药癌细胞的潜在治疗策略。